Cervical, anal, and oral cancers are caused by persistent human papillomavirus (HPV) infections. The tumors develop from pre-malignant lesions that are especially common with immunosuppression that occurs post-transplantation and with AIDS. For example, HPV-associated anal dysplasia has emerged with high frequency in the HIV-infected population. Current medical treatments for HPV are not highly effective and no treatment is specifically antiviral. Without an effective therapy, millions of women and men will develop serious and life-threatening disease each year. HPV proteins represent targets for therapeutic intervention. The viral E6 protein has multiple activities and is essential for viral replication and cellular transformation. Several E6-binding proteins present a common amino acid sequence arranged in a helical structure to bind E6, and this site represents a rationale target for antiviral therapy. The goal of this project is to use a robust assay we have developed to identify inhibitors of the HPV-16 E6 protein. The screening will initially use an in vitro assay to test a large, diverse library of small compounds. This screen will be followed by cell-based assays to evaluate the biological activities of the best hits. These results will be used to develop a quantitative structure-activity relationship (QSAR) for iterative selection of increasingly potent E6 inhibitors. This high-throughput screen should identify new chemistries and compounds in a hit-to-lead program for E6 inhibitors. It is critical for drug development to identify and characterize multiple chemical scaffolds to increase the likelihood of identifying a pharmacologically suitable compound. The expected result of this project is a lead inhibitor that can be taken into a clinical development program. The goal of these investigations is to identify a pre-clinical drug candidate that can be advanced to treat cervical, anogenital, oropharyngeal, and head and neck cancers and their precursor lesions. This translational research program is responsive to PA-04-157, which "encourages novel approaches to discovery and preclinical development of novel therapeutic agents". Success would impact the health of millions of women and men afflicted with HPV infections and associated malignancies. [unreadable] [unreadable] [unreadable]